Long term drug delivery devices with polyurethane-based polymers and their manufacture

ABSTRACT

This invention is related to the use of polyurethane-based polymer as a drug delivery device to deliver biologically active compounds at a constant rate for an extended period of time and methods of manufactures thereof. The device is very biocompatible and biostable, and is useful as an implant in patients (humans and animals) for the delivery of appropriate bioactive substances to tissues or organs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.12/912,655, filed Oct. 26, 2010, which is a Continuation of U.S. patentapplication Ser. No. 12/242,497, filed Sep. 30, 2008, the contents ofwhich are incorporated herein by reference in their entirety.

BACKGROUND

Due to its excellent biocompatibility, biostability and physicalproperties, polyurethane or polyurethane-containing polymers have beenused to fabricate a large number of implantable devices, includingpacemaker leads, artificial hearts, heart valves, stent coverings,artificial tendons, arteries and veins. Formulations for delivery ofactive agents using polyurethane implantable devices, however, require aliquid medium or carrier for the diffusion of the drug at a zero orderrate.

SUMMARY

Described herein are methods and compositions based on the unexpecteddiscovery that solid formulations comprising one or more active agentscan be used at the core of a polyurethane implantable device such thatthe active agent is released in a controlled-release, zero-order mannerfrom the implantable device. The active agents and polyurethane coatingcan be selected based on various physical parameters, and then therelease rate of the active from the implantable device can be optimizedto a clinically-relevant release rate based on clinical and/or in vitrotrials.

One embodiment is directed to a method for delivering an active agent ina subject, comprising: implanting an implantable device into thesubject, wherein the implantable device comprises an active agentsurrounded by a polyurethane-based polymer, wherein thepolyurethane-based polymer is selected according to one or more physicalproperties that allow for optimized release of the active agent from theimplantable device after implantation into the subject. In a particularembodiment, the implantable device further comprising one or morepharmaceutically acceptable carriers. In a particular embodiment, thepolyurethane-based polymer is selected based on its equilibrium watercontent or flex modulus. In a particular embodiment, thepolyurethane-based polymer is selected based on the molecular weight ofthe active agent.

One embodiment is directed to a drug delivery device for the controlledrelease of at least one active agent over an extended period of time toproduce local or systemic pharmacological effects, comprising: a) apolyurethane-based polymer formed to define a hollow space, wherein thepolyurethane-based polymer comprises one or more functional groupsselected from the group consisting of: hydrophilic pendant groups,hydrophobic pendant groups, and mixtures thereof, and wherein thefunctional groups determine the degree to which the polymer ishydrophobic or hydrophilic; and b) a solid drug formulation comprisingat least one active agent and optionally one or more pharmaceuticallyacceptable carriers, wherein the solid drug formulation is in the hollowspace of the cylindrically shaped reservoir, and wherein the polymerproperties and the water solubility characteristics of the at least oneactive agent are chosen to provide a desired release rate of the activeagent from the device after implantation. In a particular embodiment,the drug delivery device is conditioned and primed under conditionschosen to match the water solubility characteristics of the at least oneactive agent. In a particular embodiment, the conditioning and primingconditions include the use of an aqueous medium (e.g., a salinesolution) when the at least one active agent is hydrophilic. In aparticular embodiment, the conditioning and priming conditions includethe use of a hydrophobic medium (e.g., an oil-based medium) when the atleast one active agent is hydrophobic. In a particular embodiment, theat least one active agent is selected from the group consisting of:drugs that can act on the central nervous system, psychic energizers,tranquilizers, anti-convulsants, muscle relaxants, anti-parkinsonagents, analgesics, anti-inflammatory agents, anesthetics,antispasmodics, muscle contractants, anti-microbials, anti-malarials,hormonal agents, sympathomimetics, cardiovascular agents, diuretics andantiparasitic agents. In a particular embodiment, the hydrophilicpendant groups are selected from the group consisting of: ionic,carboxyl, ether and hydroxyl groups. In a particular embodiment, thehydrophobic pendant groups are selected from the group consisting of:alkyl and siloxane groups. In a particular embodiment, the solid drugformulation comprises a pharmaceutically acceptable carrier (e.g.,stearic acid). In a particular embodiment, the polyurethane-basedpolymer is thermoplastic polyurethane or thermoset polyurethane. In aparticular embodiment, the thermoplastic polyurethane comprisesmacrodiols, diisocyanates, difunctional chain extenders or mixturesthereof. In a particular embodiment, the thermoset polyurethanecomprises multifunctional polyols, isocyanates, chain extenders ormixtures thereof. In a particular embodiment, the thermoset polyurethanecomprises a polymer chain that contains unsaturated bonds, and whereinappropriate crosslinkers and/or initiators are used to crosslink polymersubunits. In a particular embodiment, the appropriate conditioning andpriming parameters can be selected to establish the desired deliveryrates of the at least one active agent, wherein the priming parametersare time, temperature, conditioning medium and priming medium.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of an implant with two open ends.

FIG. 2 is a side view of pre-fabricated end plugs used to plug theimplants.

FIG. 3 is a side view of an implant with one open end.

FIG. 4 is a graph of the elution rate of histrelin using an implant.

FIG. 5 is a graph of the elution rate of naltrexone from an implant.

FIG. 6 is a graph of the elution rate of naltrexone from polyurethaneimplants.

FIG. 7 is a graph of the elution rate of LHRH agonist (histrelin) from apolyurethane implant.

FIG. 8 is a graph of the elution rate of clonidine from a polyurethaneimplant.

FIGS. 9A and 9B are graphs showing elution from Carbothane® PC-3575A.FIG. 9A shows sections from the beginning, middle and end of a sectionof tubing. Elution was performed in a water bath or orbital shaker. FIG.9B is a graph of the release rate of risperidone from Carbothane®PC-3575A polyurethane implants (Flex Modulus 620 psi) prepared fromtubing sections representing the beginning, middle and end of a coil oftubing as part of an assessment of the uniformity of the material withina particular lot. Samples were evaluated weekly for one year for elutionusing a water bath. All implants were of equivalent geometry and drugload.

FIG. 10 is a graph of the release rate of risperidone from Carbothane®PC-3575A polyurethane implants (Flex Modulus 620 psi) as part of anassessment of the effect using saline versus aqueous hydroxypropylbetacellulose solution (15% in phosphate buffered saline) as the elutionmedia. Samples were evaluated weekly for 11 weeks. All implants were ofequivalent geometry and drug load.

FIGS. 11A and 11B are graphs comparing the release rates of risperidonefrom Carbothane® PC-3595A polyurethane implants (Flex modulus 4500 psi)to Tecophilic® HP-60D-20 polyurethane implants (EWC, 14.9%) as part ofthe evaluation of the release of the active from either hydrophilic andhydrophobic polyurethane materials. Samples were evaluated weekly for 22weeks for the Carbothane® implant. Samples were evaluated weekly for 15weeks for the Tecophilic® implant. All implants were of equivalentgeometry and drug load. FIG. 11B is a graph of the release rate ofrisperidone from Tecophilic® HP-60D-20 polyurethane implants (EWC,14.9%) alone, sampled weekly for 15 weeks.

FIG. 12 is a graph comparing the release rates of risperidone fromTecoflex® EG-80A polyurethane implants (Flex Modulus 1000 psi) and twogrades of Tecophilic® polyurethane implants, HP-60D-35 and HP-60D-60(EWC, 23.6% and 30.8%, respectively). All were sampled weekly for 10weeks. All implants were of equivalent geometry and drug load.

FIG. 13 is a graph of the release rate of risperidone from Carbothane®PC-3575A polyurethane implants (Flex Modulus 620 psi) that served as invitro controls for implants used in the beagle dog study described inExample 8. The in vitro elution study of these implants was initiated onthe date of implantation of the subject implants as part of anassessment of in vivo-in vitro correlation.

FIG. 14 is a graph of the in vivo plasma concentration of risperidone inthe beagle dog study described in Example 8. The lower plot representsthe average plasma concentration achieved in dogs implanted with oneCarbothane® PC-3575A polyurethane implant (Flex Modulus 620 psi). Theupper plot represents the average plasma concentration achieved in dogsimplanted with two Carbothane® PC-3575A polyurethane implants (FlexModulus 620 psi).

DETAILED DESCRIPTION

To take the advantage of the excellent properties of polyurethane-basedpolymers, the present invention is directed to the use ofpolyurethane-based polymers as drug delivery devices for releasing drugsat controlled rates for an extended period of time to produce local orsystemic pharmacological effects. The drug delivery device can comprisea cylindrically-shaped reservoir surrounded by polyurethane-basedpolymer that controls the delivery rate of the drug inside thereservoir. The reservoir contains a formulation, e.g., a solidformulation, comprising one or more active ingredients and, optionally,pharmaceutically acceptable carriers. The carriers are formulated tofacilitate the diffusion of the active ingredients through the polymerand to ensure the stability of the drugs inside the reservoir.

A polyurethane is any polymer consisting of a chain of organic unitsjoined by urethane links. Polyurethane polymers are formed by reacting amonomer containing at least two isocyanate functional groups withanother monomer containing at least two alcohol groups in the presenceof a catalyst. Polyurethane formulations cover an extremely wide rangeof stiffness, hardness, and densities.

Polyurethanes are in the class of compounds called “reaction polymers,”which include epoxies, unsaturated polyesters and phenolics. A urethanelinkage is produced by reacting an isocyanate group, —N═C═O with ahydroxyl (alcohol) group, —OH. Polyurethanes are produced by thepolyaddition reaction of a polyisocyanate with a polyalcohol (polyol) inthe presence of a catalyst and other additives. In this case, apolyisocyanate is a molecule with two or more isocyanate functionalgroups, R—(N═C═O)_(n≧2) and a polyol is a molecule with two or morehydroxyl functional groups, R′—(OH)_(n≧2). The reaction product is apolymer containing the urethane linkage, —RNHCOOR′—. Isocyanates reactwith any molecule that contains an active hydrogen. Importantly,isocyanates react with water to form a urea linkage and carbon dioxidegas; they also react with polyetheramines to form polyureas.

Polyurethanes are produced commercially by reacting a liquid isocyanatewith a liquid blend of polyols, catalyst, and other additives. These twocomponents are referred to as a polyurethane system, or simply a system.The isocyanate is commonly referred to in North America as the “A-side”or just the “iso,” and represents the rigid backbone (or “hard segment”)of the system. The blend of polyols and other additives is commonlyreferred to as the “B-side” or as the “poly,” and represents thefunctional section (or “soft segment”) of the system. This mixture mightalso be called a “resin” or “resin blend.” Resin blend additives caninclude chain extenders, cross linkers, surfactants, flame retardants,blowing agents, pigments and fillers. In drug delivery applications, the“soft segments” represent the section of the polymer that imparts thecharacteristics that determine the diffusivity of an activepharmaceutical ingredient (API) through that polymer.

The elastomeric properties of these materials are derived from the phaseseparation of the hard and soft copolymer segments of the polymer, suchthat the urethane hard segment domains serve as cross-links between theamorphous polyether (or polyester) soft segment domains. This phaseseparation occurs because the mainly non-polar, low-melting softsegments are incompatible with the polar, high-melting hard segments.The soft segments, which are formed from high molecular weight polyols,are mobile and are normally present in coiled formation, while the hardsegments, which are formed from the isocyanate and chain extenders, arestiff and immobile. Because the hard segments are covalently coupled tothe soft segments, they inhibit plastic flow of the polymer chains, thuscreating elastomeric resiliency. Upon mechanical deformation, a portionof the soft segments are stressed by uncoiling, and the hard segmentsbecome aligned in the stress direction. This reorientation of the hardsegments and consequent powerful hydrogen-bonding contributes to hightensile strength, elongation, and tear resistance values.

The polymerization reaction is catalyzed by tertiary amines, such as,for example, dimethylcyclohexylamine, and organometallic compounds, suchas, for example, dibutyltin dilaurate or bismuth octanoate. Furthermore,catalysts can be chosen based on whether they favor the urethane (gel)reaction, such as, for example, 1,4-diazabicyclo[2.2.2]octane (alsocalled DABCO or TEDA), or the urea (blow) reaction, such asbis-(2-dimethylaminoethyl)ether, or specifically drive the isocyanatetrimerization reaction, such as potassium octoate.

Isocyanates with two or more functional groups are required for theformation of polyurethane polymers. Volume wise, aromatic isocyanatesaccount for the vast majority of global diisocyanate production.Aliphatic and cycloaliphatic isocyanates are also important buildingblocks for polyurethane materials, but in much smaller volumes. Thereare a number of reasons for this. First, the aromatically-linkedisocyanate group is much more reactive than the aliphatic one. Second,aromatic isocyanates are more economical to use. Aliphatic isocyanatesare used only if special properties are required for the final product.Light stable coatings and elastomers, for example, can only be obtainedwith aliphatic isocyanates. Aliphatic isocyanates also are favored inthe production of polyurethane biomaterials due to their inherentstability and elastic properties.

Examples of aliphatic and cycloaliphatic isocyanates include, forexample, 1,6-hexamethylene diisocyanate (HDI),1-isocyanato-3-isocyanatomethyl-3,5,5-trimethyl-cyclohexane (isophoronediisocyanate, IPDI), and 4,4′-diisocyanato dicyclohexylmethane (H₁₂MDI).They are used to produce light stable, non-yellowing polyurethanecoatings and elastomers. H₁₂MDI prepolymers are used to produce highperformance coatings and elastomers with optical clarity and hydrolysisresistance. Tecoflex®, Tecophilic® and Carbothane® polyurethanes are allproduced from H₁₂MDI prepolymers.

Polyols are higher molecular weight materials manufactured from aninitiator and monomeric building blocks, and, where incorporated intopolyurethane systems, represent the “soft segments” of the polymer. Theyare most easily classified as polyether polyols, which are made by thereaction of epoxides (oxiranes) with an active hydrogen containingstarter compounds, or polyester polyols, which are made by thepolycondensation of multifunctional carboxylic acids and hydroxylcompounds.

Tecoflex® polyurethanes and Tecophilic® polyurethanes are cycloaliphaticpolymers and are of the types produced from polyether-based polyols. Forthe Tecoflex® polyurethanes, the general structure of the polyol segmentis represented as,

O—(CH₂—CH₂—CH₂—CH₂)_(x)—O—

whereby an increase in “x” represents a increase in flexibility(decreased “Flex Modulus”; “FM”), yielding FM ranging from about1000-92,000 psi. From the standpoint of drug release from thesematerials, the release of a relatively hydrophobic API decreases as theFM increases.

For the Tecophilic® (hydrophilic) polyurethanes, the general structureof the polyol segment is represented as,

—[O—(CH₂)_(n)]_(x)—O—

whereby increases in “n” and “x” represent variations in hydrophilicity,and yield equilibrium water contents (% EWC) ranging from about 5%-43%.From the standpoint of drug release from these materials, the release ofa relatively hydrophilic API increases as the % EWC increases.

Specialty polyols include, for example, polycarbonate polyols,polycaprolactone polyols, polybutadiene polyols, and polysulfidepolyols.

Carbothane® polyurethanes are cycloaliphatic polymers and are of thetypes produced from polycarbonate-based polyols. The general structureof the polyol segment is represented as,

O—[(CH₂)₆—CO₃]_(n)—(CH₂)—O—

whereby an increase in “n” represents a increase in flexibility(decreased FM), yielding FM ranging from about 620-92,000 psi. From thestandpoint of drug release from these materials, the release of arelatively hydrophobic API will decrease as the FM increases.

Chain extenders and cross linkers are low molecular weight hydroxyl- andamine-terminated compounds that play an important role in the polymermorphology of polyurethane fibers, elastomers, adhesives and certainintegral skin and microcellular foams. Examples of chain extendersinclude, for example, ethylene glycol, 1,4-butanediol (1,4-BDO or BDO),1,6-hexanediol, cyclohexane dimethanol and hydroquinonebis(2-hydroxyethyl)ether (HQEE). All of these glycols form polyurethanesthat phase separate well, form well-defined hard segment domains, andare melt processable. They are all suitable for thermoplasticpolyurethanes with the exception of ethylene glycol, since its derivedbis-phenyl urethane undergoes unfavorable degradation at high hardsegment levels. Tecophilic®, Tecoflex® and Carbothane® polyurethanes allincorporate the use of 1,4-butanediol as the chain extender.

The current invention provides a drug delivery device that can achievethe following objectives: a controlled-release rate (e.g., zero-orderrelease rate) to maximize therapeutic effects and minimize unwanted sideeffects, an easy way to retrieve the device if it is necessary to endthe treatment, an increase in bioavailability with less variation inabsorption and no first pass metabolism.

The release rate of the drug is governed by the Fick's Law of Diffusionas applied to a cylindrically shaped reservoir device (cartridge). Thefollowing equation describes the relationship between differentparameters:

$\frac{M}{t} = \frac{2\pi \; h\; p\; \Delta \; C}{\ln ( {r_{o}/r_{i}} )}$

where:

-   -   dM/dt: drug release rate;    -   h: length of filled portion of device;    -   ΔC: concentration gradient across the reservoir wall;    -   r_(o)/r_(i): ratio of outside to inside radii of device; and    -   p: permeability coefficient of the polymer used.

The permeability coefficient is primarily regulated by thehydrophilicity or hydrophobicity of the polymer, the structure of thepolymer, and the interaction of drug and the polymer. Once the polymerand the active ingredient are selected, p is a constant, h, r_(o), andr_(i) are fixed and kept constant once the cylindrically-shaped deviceis produced. ΔC is maintained constant.

To keep the geometry of the device as precise as possible, the device,e.g., a cylindrically-shaped device, can be manufactured throughprecision extrusion or precision molding process for thermoplasticpolyurethane polymers, and reaction injection molding or spin castingprocess for thermosetting polyurethane polymers.

The cartridge can be made with either one end closed or both ends open.The open end can be plugged with, for example, pre-manufactured endplug(s) to ensure a smooth end and a solid seal, or, in the case ofthermoplastic polyurethanes, by using heat-sealing techniques known tothose skilled in the art. The solid actives and carriers can becompressed into pellet form to maximize the loading of the actives.

To identify the location of the implant, radiopaque material can beincorporated into the delivery device by inserting it into the reservoiror by making it into end plug to be used to seal the cartridge.

Once the cartridges are sealed on both ends with the filled reservoir,they are optionally conditioned and primed for an appropriate period oftime to ensure a constant delivery rate.

The conditioning of the drug delivery devices involves the loading ofthe actives (drug) into the polyurethane-based polymer that surroundsthe reservoir. The priming is done to stop the loading of the drug intothe polyurethane-based polymer and thus prevent loss of the activebefore the actual use of the implant. The conditions used for theconditioning and priming step depend on the active, the temperature andthe medium in which they are carried out. The conditions for theconditioning and priming may be the same in some instances.

The conditioning and priming step in the process of the preparation ofthe drug delivery devices is done to obtain a determined rate of releaseof a specific drug. The conditioning and priming step of the implantcontaining a hydrophilic drug can be carried out in an aqueous medium,e.g., in a saline solution. The conditioning and priming step of a drugdelivery device comprising a hydrophobic drug is usually carried out ina hydrophobic medium such as, for example, an oil-based medium. Theconditioning and priming steps can be carried out by controlling threespecific factors, namely the temperature, the medium and the period oftime.

A person skilled in the art would understand that the conditioning andpriming step of the drug delivery device is affected by the medium inwhich the device is placed. A hydrophilic drug can be conditioned andprimed, for example, in an aqueous solution, e.g., in a saline solution.Histrelin and Naltrexone implants, for example, have been conditionedand primed in saline solution, more specifically, conditioned in salinesolution of 0.9% sodium content and primed in saline solution of 1.8%sodium chloride content.

The temperature used to condition and prime the drug delivery device canvary across a wide range of temperatures, e.g., about 37° C.

The time period used for the conditioning and priming of the drugdelivery devices can vary from about a single day to several weeksdepending on the release rate desired for the specific implant or drug.The desired release rate is determined by one of skill in the art withrespect to the particular active agent used in the pellet formulation.

A person skilled in the art will understand the steps of conditioningand priming the implants are to optimize the rate of release of the drugcontained within the implant. As such, a shorter time period spent onthe conditioning and the priming of a drug delivery device results in alower rate of release of the drug compared to a similar drug deliverydevice that has undergone a longer conditioning and priming step.

The temperature in the conditioning and priming step will also affectthe rate of release in that a lower temperature results in a lower rateof release of the drug contained in the drug delivery device whencompared to a similar drug delivery device that has undergone atreatment at a higher temperature.

Similarly, in the case of aqueous solutions, e.g., saline solutions, thesodium chloride content of the solution determines what type of rate ofrelease will be obtained for the drug delivery device. Morespecifically, a lower content of sodium chloride results in a higherrate of release of drug when compared to a drug delivery device that hasundergone a conditioning and priming step where the sodium chloridecontent was higher.

The same conditions apply for hydrophobic drugs where the maindifference in the conditioning and priming step is that the conditioningand priming medium is a hydrophobic medium, more specifically anoil-based medium.

The drug (actives) that can be delivered include drugs that can act onthe central nervous system, psychic energizers, tranquilizers,anti-convulsants, muscle relaxants, anti-parkinson, analgesic,anti-inflammatory, anesthetic, antispasmodic, muscle contractants,anti-microbials, anti-malarials, hormonal agents, sympathomimetic,cardiovascular, diuretics, anti-parasitic and the like. Drugs alsoinclude drugs for use in urology, e.g., to treat or prevent a urologicaldisorder or for contraception, such as, but not limited to, valrubicin,doxorubicin, bladder cancer cytotoxic agents, 5-amino salycilic acid(5-ASA), hydrocortisone, dexamethasone, anti-inflammatory agents,trospium chloride, tamsulosin, oxybutinin, and any hormone (such as, forexample, ethinyl estradiol, levonorgestrel, estradiol, testosterone, andthe like). Urological uses include, but are not limited to, for example,bladder cancer, interstitial cystitis, bladder inflammation, overactivebladder, benign prostatic hyperplasia (BPH), contraception,post-menopausal symptoms and hypogonatism. Implantable devices for usein bladder can range in size from, for example, about 2 mm to about 10mm, from about 3 mm to about 6 mm, or about 2.7 mm in diameter and up toabout 50 mm in length.

The current invention focuses on the application of polyurethane-basedpolymers, thermoplastics or thermosets, to the creation of implantabledrug devices to deliver biologically active compounds at controlledrates for prolonged period of time. Polyurethane polymers can be madeinto, for example, cylindrical hollow tubes with one or two open endsthrough extrusion, (reaction) injection molding, compression molding, orspin-casting (see e.g., U.S. Pat. Nos. 5,266,325 and 5,292,515),depending on the type of polyurethane used.

Thermoplastic polyurethane can be processed through extrusion, injectionmolding or compression molding. Thermoset polyurethane can be processedthrough reaction injection molding, compression molding, orspin-casting. The dimensions of the cylindrical hollow tube should be asprecise as possible.

Polyurethane-based polymers are synthesized from multi-functionalpolyols, isocyanates and chain extenders. The characteristics of eachpolyurethane can be attributed to its structure.

Thermoplastic polyurethanes are made of macrodiols, diisocyanates, anddifunctional chain extenders (e.g., U.S. Pat. Nos. 4,523,005 and5,254,662). Macrodiols make up the soft domains. Diisocyanates and chainextenders make up the hard domains. The hard domains serve as physicalcrosslinking sites for the polymers. Varying the ratio of these twodomains can alter the physical characteristics of the polyurethanes,e.g., the flex modulus.

Thermoset polyurethanes can be made of multifunctional (greater thandifunctional) polyols and/or isocyanates and/or chain extenders (e.g.,U.S. Pat. Nos. 4,386,039 and 4,131,604). Thermoset polyurethanes canalso be made by introducing unsaturated bonds in the polymer chains andappropriate crosslinkers and/or initiators to do the chemicalcrosslinking (e.g., U.S. Pat. No. 4,751,133). By controlling the amountsof crosslinking sites and how they are distributed, the release rates ofthe actives can be controlled.

Different functional groups can be introduced into the polyurethanepolymer chains through the modification of the backbones of polyolsdepending on the properties desired. Where the device is used for thedelivery of water soluble drugs, hydrophilic pendant groups such asionic, carboxyl, ether, and hydroxy groups are incorporated into thepolyols to increase the hydrophilicity of the polymer (e.g., U.S. Pat.Nos. 4,743,673 and 5,354,835). Where the device is used for the deliveryof hydrophobic drugs, hydrophobic pendant groups such as alkyl, siloxanegroups are incorporated into the polyols to increase the hydrophobicityof the polymer (e.g., U.S. Pat. No. 6,313,254). The release rates of theactives can also be controlled by the hydrophilicity/hydrophobicity ofthe polyurethane polymers.

For thermoplastic polyurethanes, precision extrusion and injectionmolding are the preferred choices to produce two open-end hollow tubes(FIG. 1) with consistent physical dimensions. The reservoir can beloaded freely with appropriate formulations containing actives andcarriers or filled with pre-fabricated pellets to maximize the loadingof the actives. One open end needs to be sealed first before the loadingof the formulation into the hollow tube. To seal the two open ends, twopre-fabricated end plugs (FIG. 2) can be used. The sealing step can beaccomplished through the application of heat or solvent or any othermeans to seal the ends, preferably permanently.

For thermoset polyurethanes, precision reaction injection molding orspin casting is the preferred choice depending on the curing mechanism.Reaction injection molding is used if the curing mechanism is carriedout through heat and spin casting is used if the curing mechanism iscarried out through light and/or heat. Hollow tubes with one open end(FIG. 3), for example, can be made by spin casting. Hollow tubes withtwo open ends, for example, can be made by reaction injection molding.The reservoir can be loaded in the same way as the thermoplasticpolyurethanes.

To seal an open end, an appropriate light-initiated and/orheat-initiated thermoset polyurethane formulation can be used to fillthe open end, and this is cured with light and/or heat. A pre-fabricatedend plug, for example, can also be used to seal the open end by applyingan appropriate light-initiated and/or heat-initiated thermosetpolyurethane formulation on to the interface between the pre-fabricatedend plug and the open end, and curing it with the light and/or heat orany other means to seal the ends, preferably permanently.

The final process involves the conditioning and priming of the implantsto achieve the delivery rates required for the actives. Depending uponthe types of active ingredient, hydrophilic or hydrophobic, theappropriate conditioning and priming media is chosen. Water-based mediaare preferred for hydrophilic actives, and oil-based media are preferredfor hydrophobic actives.

As a person skilled in the art would readily know many changes can bemade to the preferred embodiments of the invention without departingfrom the scope thereof. It is intended that all matter contained hereinbe considered illustrative of the invention and not it a limiting sense.

EXEMPLIFICATION Example 1

Tecophilic® polyurethane polymer tubes are supplied by ThermedicsPolymer Products and manufactured through a precision extrusion process.Tecophilic® polyurethane is a family of aliphatic polyether-basedthermoplastic polyurethane that can be formulated to differentequilibrium water contents (EWC) of up to 150% of the weight of dryresin. Extrusion grade formulations are designed to provide maximumphysical properties of thermoformed tubing or other components. Anexemplary tube and end cap structures are depicted in FIGS. 1-3.

The physical data for the polymers is provided below as made availableby Thermedics Polymer Product (tests conducted as outlined by AmericanSociety for Testing and Materials (ASTM), Table 1).

TABLE 1 Tecophilic ® Typical Physical Test Data HP- HP- HP- HP- ASTM60D-20 60D-35 60D-60 93A-100 Durometer D2240 43D 42D 41D 83A (ShoreHardness) Spec D792  1.12 1.12 1.15 1.13 Gravity Flex D790  4,300 4,0004,000 2,900 Modulus (psi) Ultimate D412  8,900 7,800 8,300 2,200 TensileDry (psi) Ultimate D412  5,100 4,900 3,100 1,400 Tensile Wet (psi)Elongation D412  430 450 500 1,040 Dry (%) Elongation D412  390 390 300620 Wet (%)

HP-60D-20 is extruded to tubes with thickness of 0.30 mm with insidediameter of 1.75 mm. The tubes are then cut into 25 mm in length. Oneside of the tube is sealed with heat using a heat sealer. The sealingtime is less than one minute. Four pellets of histrelin acetate areloaded into the tube. Each pellet weighs approximately 13.5 mg for atotal of 54 mg. Each pellet is comprised of a mixture of 98% histrelinand 2% stearic acid. The second end open of the tube is sealed with heatin the same way as for the first end. The loaded implant is thenconditioned and primed. The conditioning takes place at room temperaturein a 0.9% saline solution for one day. Upon completion of theconditioning, the implant undergoes priming. The priming takes place atroom temperatures in a 1.8% saline solution for one day. Each implant istested in vitro in a medium selected to mimic the pH found in the humanbody. The temperature of the selected medium was kept at approximately37° C. during the testing. The release rates are shown on FIG. 4 andTable 2.

TABLE 2 Histrelin Elution Rates WEEKS OF HP-60D-20 ELUTION (μg/day) 1451.733 2 582.666 3 395.9 4 310.29 5 264.92 6 247.17 7 215.93 8 201.78 9183.22 10 174.99 11 167.72 12 158.37 13 153.95 14 146.46 15 139.83 16129.6 17 124.46 18 118.12 19 120.35

Example 2

HP-60D-35 is extruded to tubes with thickness of 0.30 mm with insidediameter of 1.75 mm. The tubes are then cut into 32 mm in length. Oneside of the tube is sealed with heat using a heat sealer. The sealingtime is less than one minute. Six pellets of naltrexone are loaded intothe tubes and both open sides of the tubes are sealed with heat. Eachpellet weighs approximately 15.0 mg for a total of 91 mg. The second endopen of the tube is sealed with heat in the same way as for the firstend. The loaded implant is then conditioned and primed. The conditioningtakes place at room temperature in a 0.9% saline solution for one week.Upon completion of the conditioning, the implant undergoes priming. Thepriming takes place at room temperatures in a 1.8% saline solution forone week. Each implant is tested in vitro in a medium selected to mimicthe pH found in the human body. The temperature of the selected mediumwas kept at approximately 37° C. during the testing. The release ratesare shown on FIG. 5 and Table 3.

TABLE 3 Naltrexone Elution Rates WEEKS OF HP-60D-35-1 HP-60D-35-2HP-60D-35-3 RELEASE (μg/day) (μg/day) (μg/day) 0 1 1529.26 767.381400.95 2 1511.77 1280.03 1498.86 3 1456.01 1635.97 1449.49 4 1378.271607.13 1500.42 5 1393.05 1614.52 1558.37 6 1321.71 1550.39 1436.03 71273.07 1424.24 1300.73 8 1172.82 1246.48 1221.57

Example 3

In FIG. 6 there is a comparison of the release rates of naltrexone invitro using two grades of polymer at two different water contents. Threeruns were carried out and analyzed where the polymer of the implant hada water content of 24% and three runs were carried out where the polymerof the implant had a water content of 30%. The release rates wereplotted against time. The polymer used for the runs at 24% water contentwas Tecophilic® HP-60-D35 from Thermedics. The polymer used for the runsat 30% water content was Tecophilic® HP-60-D60 from Thermedics. The dataobtained in this example demonstrate the good reproducibility of theimplants as prepared according to the present invention.

Example 4

FIG. 7 shows a plot of the release rate of histrelin (LHRH agonist)versus time. The polymer in this example had a water content of 15%. Thepolymer used was Tecophilic® HP-60-D20 from Thermedics. The data pointswere taken weekly.

Example 5

FIG. 8 shows a plot of the release rate of clonidine versus time. Thepolymer in this example has a water content of 15%. The polymer used wasTecophilic® HP-60-D20 from Thermedics. The data points were takenweekly.

Example 6

Tables 4A-C show release rates of active agents from three differentclasses of polyurethane compounds (Tecophilic®, Tecoflex® andCarbothane®). The release rates have been normalized to surface area ofthe implant, thereby adjusting for slight differences in the size of thevarious implantable devices. The active agents were selected to cover arange of solubilities (as indicated by the varying Log P values; for thepurposes of the data provided, a Log P value of greater than about 2.0is considered to be not readily soluble in aqueous solution) andmolecular weights. The polyurethanes were selected to have varyingaffinities for water soluble active agents and varying flexibility (asindicated by the variation in flex modulus).

For applications of the polyurethanes useful for the devices and methodsdescribed herein, the polyurethane exhibits physical properties suitablefor the specific active agent to be delivered. Polyurethanes areavailable or can be prepared, for example, with a range of EWCs or flexmoduli (Table 4). Tables 4A-C show normalized release rates for variousactive ingredients from polyurethane compounds. Tables 4D-F show thenon-normalized release rates for the same active ingredients, togetherwith implant composition.

TABLE 4A Polyurethane Type Tecophilic Polyurethane Grade HP-60D-60HP-60D-35 HP-60D-20 HP-60D-10 HP-60D-05 % EWC/Flex Modulus 31% EWC 24%EWC 15% EWC 8.7% EWC 5.5% EWC Active Relative Water SolubilityOctreotide Very soluble, — 2022 758 11 0 Acetate Log P = 0.43 μg/day/cm²μg/day/cm² μg/day/cm² 10% HPC, 2% SA, (M.W. 1019) 2% SA 5% HPC, 2% SA;10% HPC, 2% SA, 50 mg API 50 mg API 50 mg API 50 mg API Histrelin Verysoluble 309 248 93 — — Acetate Log P = (n/a) μg/day/cm² μg/day/cm²μg/day/cm² (M.W. 1323) 2% SA 2% SA 2% SA 50 mg API 50 mg API 50 mg APISelegiline Freely soluble — — 294 — — HCL Log P = (n/a) μg/day/cm² (M.W.224) 2% SA 66.8 mg API Dexamethasone Log P = 1.93 — — 85 — — (M.W. 392)μg/day/cm² 10% CC, 2% SA, 47.5 mg API Naltrexone Log P = 2.07 883 704263 127 12.7 Base μg/day/cm² μg/day/cm² μg/day/cm² μg/day/cm² μg/day/cm²(M.W. 285) 10% CC, 2% SA + 2% SA 10% CC, 2% SA, 10% CC, 2% SA + 10% CC,2% SA, PEG 400, 79.2 mg API 91.3 mg API 193.6 mg API PEG 400, 197.1 mgAPI

44.6 mg API Metolazone Log P = 2.50 — — 50 — — (M.W. 366) μg/day/cm² 10%CC, 2% SA, 82.7 mg API Clonidine Log P = 2.56 — — 1011 — — Baseμg/day/cm² (M.W. 230) 2% SA ~50 mg API Risperidone Log P = 3.28 — — 149— — (M.W. 410) μg/day/cm² 10% CC, 2% SA, 28.5 mg API

indicates data missing or illegible when filed

TABLE 4B Polyurethane Type Tecoflex Polyurethane Grade Relative EG-85AEG 100A EG-65D Water % EWC/Flex Modulus Active Solubility F.M.: 2,300F.M.: 10,000 F.M.: 37,000 Octreotide Very soluble, 16 μg/day/cm² — —Acetate Log P = 0.43 10% HPC, (M.W. 1019) 2% SA,   50 mg API HistrelinVery soluble — 0.3 — Acetate Log P = (n/a) μg/day/cm² (M.W. 1323)  2% SA  50 mg API Selegiline Freely 1518 7.2 4.1 HCL soluble μg/day/cm²μg/day/cm² μg/day/cm² (M.W. 224) Log P = (n/a)  2% SA  2% SA  2% SA 67.2mg API 63.5 mg API 63.1 mg API Dexameth- Log P = 1.93 40 μg/day/cm² 2.60.5 asone 10% CC, μg/day/cm² μg/day/cm² (M.W. 392)  2% SA, 10% CC, 10%CC, 47.3 mg API  2% SA,  2% SA, 54.5 mg API 53.1 mg API Naltrexone Log P= 2.07 — 23 — Base μg/day/cm² (M.W. 285) 10% CC,  2% SA, 75.5 mg APIMetolazone Log P = 2.50 32 μg/day/cm² 2.3 — (M.W. 366) 10% CC,μg/day/cm²  2% SA, 10% CC, 82.7 mg API  2% SA, 82.0 mg API Clonidine LogP = 2.56 1053 88 25 Base μg/day/cm² μg/day/cm² μg/day/cm² (M.W. 230) 20%CC, 20% CC, 20% CC,  2% SA,  2% SA,  2% SA, 80.3 mg API 65.7 mg API 66.3mg API Risperidone Log P = 3.28 146 7.6 1.9 (M.W. 410) μg/day/cm²μg/day/cm² μg/day/cm² 10% CC, 10% CC, 10% CC,  2% SA,  2% SA,  2% SA,27.9 mg API 29.8 mg API 29.7 mg API

TABLE 4C Polyurethane Type Carbothane Polyurethane Grade RelativePC-3575A PC-3595A Water % EWC/Flex Modulus Active Solubility F.M.: 620F.M.: 4,500 Octreotide Acetate Very soluble, — — (M.W. 1019) Log P =0.43 Histrelin Acetate Very soluble — 0.2 μg/day/cm² (M.W. 1323) Log P =(n/a) 2% SA   50 mg API Selegiline HCL Freely soluble  36 μg/day/cm²  15μg/day/cm² (M.W. 224) Log P = (n/a)  2% SA  2% SA 65.3 mg API 66.8 mgAPI Dexamethasone Log P = 1.93 6.2 μg/day/cm² 2.3 μg/day/cm² (M.W. 392)10% CC, 10% CC,  2% SA,  2% SA, 47.1 mg API 53.2 mg API Naltrexone BaseLog P = 2.07 — 5.5 μg/day/cm² (M.W. 285) 10% CC,  2% SA, 189.2 mg API Metolazone Log P = 2.50 8.4 μg/day/cm² 2.3 μg/day/cm² (M.W. 366) 10% CC,10% CC,  2% SA,  2% SA, 82.7 mg API 81.6 mg API Clonidine Base Log P =2.56 202 136 (M.W. 230) μg/day/cm² μg/day/cm² 20% CC, 20% CC,  2% SA, 2% SA, 66.5 mg API 64.6 mg API Risperidone Log P = 3.28  40 μg/day/cm² 11 μg/day/cm² (M.W. 410) 10% CC, 10% CC,  2% SA,  2% SA, 27.8 mg API29.7 mg API

TABLE 4D Polyurethane Tecophilic Grade HP-60D-60 HP-60D-35 HP-60D-20HP-60D-10 HP-60D-05 % EWC 31% EWC 24% EWC 15% EWC 8.7% EWC 5.5% EWCActive Relative Water Solubility Octreotide Very soluble, — 4000 μg/day1500 μg/day 25 μg/day 0 Acetate Log P = 0.43 ID: 1.80 mm ID: 1.80 mm ID:1.83 mm (M.W. 1019) Wall: 0.30 mm Wall: 0.30 mm Wall: 0.30 mm L: 30 mmL: 30 mm L: 34 mm 1.978 cm² 1.978 cm² 2.274 cm² Histrelin Very soluble500 μg/day 400 μg/day 150 μg/day — — Acetate Log P = (n/a) ID: 1.80 mmID: 1.80 mm ID: 1.80 mm (M.W. 1323) Wall: 0.30 mm Wall: 0.30 mm Wall:0.30 mm L: 24.5 mm L: 24.5 mm L; 24.5 mm 1.616 cm² 1.616 cm² 1.616 cm²Selegiline Freely soluble — — 600 μg/day — — HCL Log P = (n/a) ID: 1.80mm (M.W. 224) Wall: 0.3 mm L: 30.9 mm 2.038 cm² Dexamethasone Log P =1.93 — — 170 μg/day — — (M.W. 392) ID: 1.80 mm Wall: 0.30 mm L: 30.24 mm1.994 cm² Naltrexone Log P = 2.07 2200 μg/day 1500 μg/day 1000 μg/day500 μg/day 50 μg/day Base ID: 1.80 mm ID: 1.80 mm ID: 2.87 mm ID: 3.05mm ID: 3.05 mm (M.W. 285) Wall: 0.30 mm Wall: 0.30 mm Wall: 0.38 mmWall: 0.30 mm Wall: 0.30 mm L: 37.8 mm L: 32.3 mm L: 37.2 mm L: 37.3 mmL: 37.4 mm 2.492 cm² 2.130 cm² 3.796 cm² 3.924 cm² 3.934 cm² MetolazoneLog P = 2.50 124 μg/day (M.W. 366) ID: 1.80 mm Wall: 0.30 mm L: 37.4 mm2.466 cm² Clonidine Log P = 2.56 — — 2000 μg/day — — Base ID: 1.80 mm(M.W. 230) Wall: 0.30 mm L: 30.0 mm 1.978 cm² Risperidone Log P = 3.28 —— 150 μg/day — — (M.W. 410) ID: 1.80 mm Wall: 0.30 mm L: 15.24 mm 1.005cm²

TABLE 4E Polyurethane Type Tecoflex Polyurethane Grade Relative EG-85AEG 100A EG-65D Water Flex Modulus Active Solubility F.M.: 2,300 F.M.:10,000 F.M.: 37,000 Octreotide Acetate Very soluble, 30 μg/day — — (M.W.1019) Log P = 0.43 ID: 1.85 mm Wall: 0.20 mm L: 30 mm 1.931 cm²Histrelin Acetate Very soluble — 0.5 μg/day — (M.W. 1323) Log P = (n/a)ID: 1.85 mm Wall: 0.20 mm L; 25.56 mm 1.645 cm² Selegiline HCL Freelysoluble 3000 μg/day 14 μg/day 8 μg/day (M.W. 224) Log P = (n/a) ID: 1.85mm ID: 1.85 mm ID: 1.85 mm Wall: 0.20 mm Wall: 0.20 mm Wall: 0.20 mm L:30.7 mm L: 30.2 mm L: 30.4 mm 1.976 cm² 1.944 cm² 1.957 cm²Dexamethasone Log P = 1.93 80 μg/day 5 μg/day 1.0 μg/day (M.W. 392) ID:1.85 mm ID: 1.85 mm ID: 1.85 mm Wall: 0.20 mm Wall: 0.20 mm Wall: 0.20mm L: 30.9 mm L: 30.0 mm L: 30.7 mm 1.989 cm² 1.931 cm² 1.976 cm²Naltrexone Base Log P = 2.07 — 55 μg/day — (M.W. 285) ID: 1.85 mm Wall:0.20 mm L: 37.49 mm 2.413 cm² Metolazone Log P = 2.50 77 μg/day 5.5μg/day — (M.W. 366) ID: 1.85 mm ID: 1.85 mm Wall: 0.20 mm Wall: 0.20 mmL: 37.7 mm L:37.15 mm 2.427 cm² 2.391 cm² Clonidine Base Log P = 2.562000 μg/day 175 μg/day 50 μg/day (M.W. 230) ID: 1.85 mm ID: 1.85 mm ID:1.85 mm Wall: 0.20 mm Wall: 0.20 mm Wall: 0.20 mm L: 29.5 mm L: 30.8 mmL: 30.8 mm 1.899 cm² 1.983 cm² 1.983 cm² Risperidone Log P = 3.28 150μg/day 8 μg/day 2 μg/day (M.W. 410) ID: 1.85 mm ID: 1.85 mm ID: 1.85 mmWall: 0.20 mm Wall: 0.20 mm Wall: 0.20 mm L: 16.0 mm L: 16.4 mm L: 16.2mm 1.030 cm² 1.056 cm² 1.043 cm²

TABLE 4F Polyurethane Type Carbothane Polyurethane Grade RelativePC-3575A PC-3595A Water Flex Modulus Active Solubility F.M.: 620 F.M.:4,500 Octreotide Very soluble, — — Acetate Log P = 0.43 (M.W. 1019)Histrelin Very soluble — 0.4 μg/day Acetate Log P = (n/a) ID: 1.85 mm(M.W. 1323) Wall: 0.20 mm L; 25.25 mm 1.625 cm² Selegiline Freelysoluble 70 μg/day 30 μg/day HCL Log P = (n/a) ID: 1.85 mm ID: 1.85 mm(M.W. 224) Wall: 0.20 mm Wall: 0.20 mm L: 29.2 mm L: 30.6 mm 1.925 cm²1.970 cm² Dexameth- Log P = 1.93 12 μg/day 4.5 μg/day asone ID: 1.85 mmID: 1.85 mm (M.W. 392) Wall: 0.20 mm Wall: 0.20 mm L:30.0 mm L: 30.7 mm1.931 cm² 1.976 cm² Naltrexone Log P = 2.07 — 25 μg/day Base ID: 3.63 mm(M.W. 285) Wall: 0.18 mm L: 38.19 mm 4.569 cm² Metolazone Log P = 2.5020 μg/day 6.1 μg/day (M.W. 366) ID: 1.85 mm ID: 1.85 mm Wall: 0.20 mmWall: 0.20 mm L: 37.0 mm L: 37.02 mm 2.382 cm² 2.383 cm² Clonidine Log P= 2.56 400 μg/day 270 μg/day Base ID: 1.85 mm ID: 1.85 mm (M.W. 230)Wall: 0.20 mm Wall: 0.20 mm L: 30.8 mm L: 30.8 mm 1.983 cm² 1.983 cm²Risperidone Log P = 3.28 40 μg/day 11 μg/day (M.W. 410) ID: 1.85 mm ID:1.85 mm Wall: 0.20 mm Wall: 0.20 mm L: 15.6 mm L: 16.2 mm 1.004 cm²1.043 cm²

The solubility of an active agent in an aqueous environment can bemeasured and predicted based on its partition coefficient (defined asthe ratio of concentration of compound in aqueous phase to theconcentration in an immiscible solvent). The partition coefficient (P)is a measure of how well a substance partitions between a lipid (oil)and water. The measure of solubility based on P is often given as Log P.In general, solubility is determined by Log P and melting point (whichis affected by the size and structure of the compounds). Typically, thelower the Log P value, the more soluble the compound is in water. It ispossible, however, to have compounds with high Log P values that arestill soluble on account of, for example, their low melting point. It issimilarly possible to have a low Log P compound with a high meltingpoint, which is very insoluble.

The flex modulus for a given polyurethane is the ratio of stress tostrain. It is a measure of the “stiffness” of a compound. This stiffnessis typically expressed in Pascals (Pa) or as pounds per square inch(psi).

The elution rate of an active agent from a polyurethane compound canvary on a variety of factors including, for example, the relativehydrophobicity/hydrophilicity of the polyurethane (as indicated, forexample, by logP), the relative “stiffness” of the polyurethane (asindicated, for example, by the flex modulus), and/or the molecularweight of the active agent to be released.

Example 7 Elution of Risperidone from Polyurethane Implantable Devices

FIGS. 9-14 are graphs showing elution profiles of risperidone fromvarious implantable devices over varying periods of time.

Release rates were obtained for risperidone from Carbothane® PC-3575Apolyurethane implants (F.M. 620 psi) prepared from tubing sectionsrepresenting the beginning, middle and end of a coil of tubing as partof an assessment of the uniformity of the material within a particularlot (FIG. 9). Samples were evaluated weekly for one year. All implantswere of equivalent geometry and drug load.

Release rates were obtained for risperidone from Carbothane® PC-3575Apolyurethane implants (F.M. 620 psi) as part of an assessment of theeffect using saline versus aqueous hydroxypropyl betacellulose solution(15% in phosphate buffered saline) as the elution media (FIG. 10).Samples were evaluated weekly for 11 weeks. All implants were ofequivalent geometry and drug load.

Release rates were compared for risperidone from Carbothane® PC-3595Apolyurethane implants (F.M. 4500 psi) and Tecophilic® HP-60D-20polyurethane implants (EWC 14.9%) as part of the evaluation of therelease of the active from either hydrophilic and hydrophobicpolyurethane materials (FIGS. 11A and 11B). Samples were evaluatedweekly for 22 weeks for the Carbothane® implant. Samples were evaluatedweekly for 15 weeks for the Tecophilic® implant. All implants were ofequivalent geometry and drug load.

Release rates were compared for risperidone from Tecoflex® EG-80Apolyurethane implants (F.M. 1000 psi) and two grades of Tecophilic®polyurethane implants, HP-60D-35 and HP-60D-60 (EWC, 23.6% and 30.8%,respectively) (FIG. 12). All were sampled weekly for 10 weeks. Allimplants were of equivalent geometry and drug load.

Release rates were obtained for risperidone from Carbothane® PC-3575Apolyurethane implants (F.M. 620 psi) that served as in vitro controlsfor implants used in the beagle dog study described in Example 8. The invitro elution study of these implants was initiated on the date ofimplantation of the subject implants as part of an assessment of invivo-in vitro correlation.

Example 8 Evaluation of Polyurethane Subcutaneous Implant DevicesContaining Risperidone in Beagle Dogs

The purposes of this study are to determine the blood levels ofrisperidone from one or two implants and the duration of time theimplants will release drug. Polyurethane-based implantable devicescomprising a pellet comprising risperidone were implanted into beaglesto determine release rates of risperidone in vivo. The results of thesample analysis are summarized in Table 5 and FIG. 14. Risperidone isstill present at a high level in the dog plasma at the end of the thirdmonth. The study was conducted in accordance with WCFP's standardoperating procedures (SOPs), the protocol, and any protocol amendments.All procedure were conducted in accordance with the Guide for the Careand Use of Laboratory Animals (National Research Center, NationalAcademy Press, Washington, D.C., 1996), and approved by theInstitutional Animal Care and Use Committee in WCFP.

The implants initially contained about 80 mg of risperidone and aredesigned to deliver approximately 130 mcg/day for 3 months. The testarticle was stored at between 2-8° C. before use.

The animals were as follows:

Species: Canine

Strain: Beagle dog

Source: Guangzhou Pharm. Industril Research Institute,

Certification No: SCXK(YUE)2003-0007

Age at Initiation of Treatment: 6˜9 months

Weight: 8˜10 kg

Number and Sex: 6 males

Prior to study initiation, animals were assigned a pretreatmentidentification number. All animals were weighed before administrationonce weekly, and received cage-side observations daily by qualifiedveterinarian during acclimation period. All animals were given aclinical examination prior to selection for study. Animals with anyevidence of disease or physical abnormalities were not selected forstudy. The blood sampling was taken as Baseline at the 3rd and 2nd daybefore implant. Animals were then randomized into to 2 groups, with thedosing schedule provided as follows:

No. of Animals Dose rate Total Dose Group Dose Route Male (mcg/day) (mg)1 Subcutaneous 3 130 23 implant (single implant) 2 Subcutaneous 3 260 46implant (double implants)

Each animal was anesthetized by general anesthesia via pentobarbitalsodium at the dose of 30 mg/kg for device implantation. The drug wasreleased at a steady rate for several months. Half the animals receivedone implant (group 1) and the others received two implants (group 2). A5 cm² area of the shoulder was shaved and 2 mL of marcaine infused underthe skin to numb the area. A small incision was made on the shoulder andthe device was slid under the skin. The small incision was closed andthe animal was allowed to recover and return to his run. Over the nextfive to seven days, the implantation site was be monitored for signs ofinfection or reaction. The skin staples were removed when the skin hashealed sufficiently. At the end of three months, the devices wereremoved, just as they would clinically.

Animals were fasted at least four hours prior to blood sampling. Sinceblood sampling was done in the morning, food was withheld overnight.Blood samples were drawn using a 20G needle and collected directly intothe 5 mL tubes containing sodium heparin and maintained chilled untilcentrifugation. Samples were then centrifuged at 5000 RPM for 5 minutesat 4° C. The separated plasma was then be transferred into two 3 mL cryotubes. The samples were labeled with the actual date the sample wastaken, the corresponding study day, the dog identification and theduplicate sample designator (either A or B). Samples were kept at −20°C. until ready for analysis.

On two consecutive days, prior to implantation of the delivery device,baseline blood samples were taken. In addition, daily blood samples weretaken during the first week and weekly blood samples were taken for thethree months following implantation. Two 5 mL blood samples were drawnat each time from each dog. Blood samples were drawn from the cephalicveins primarily; with the saphenous or jugular used as a backup. Forboth the single and double implant groups, blood samples were drawn atappropriate times as outlined in Table 5 below. Analysis required atleast 2 mL of plasma, which required no less than 10 mL of blood drawnfor each sample. Analysis of plasma concentrations of risperidone wasperformed using an LC/MS assay developed for this compound. A singleassay was be run for each sample. Samples were collected, held at theappropriate condition and analyzed in batches.

TABLE 5 Concentration of Risperidone in Dog Plasma Group 1(singleimplant) Group 2(double implants) Group 1 Group 2 Date Week Day 1M011M02 1M03 2M01 2M02 2M03 Mean S.D. Mean S.D. −3 — — — — — — −2 — — — — —— 1.29 1 1 BLQ BLQ 0.26 BLQ 0.54 BLQ 0.26 / 0.54 / 1.30 1 2 0.77 BLQ0.24 0.53 1.86 0.46 0.51 0.37 0.95 0.79 1.31 1 3 1.16 0.78 0.37 1.152.70 0.92 0.77 0.40 1.59 0.97 2.01 1 4 1.26 0.79 0.66 1.21 3.85 0.940.90 0.32 2.00 1.61 2.02 1 5 1.15 0.66 1.03 1.02 3.13 0.77 0.95 0.261.64 1.30 2.03 1 6 1.14 0.58 0.52 0.97 2.96 0.79 0.75 0.34 1.57 1.202.04 1 7 1.17 0.72 0.44 0.89 3.27 0.73 0.78 0.37 1.63 1.42 2.11 2 141.26 1.03 0.38 1.15 2.81 1.01 0.89 0.46 1.66 1.00 2.18 3 21 1.09 0.700.62 1.38 3.09 0.91 0.80 0.25 1.79 1.15 2.25 4 28 1.34 0.84 1.02 1.713.55 1.10 1.07 0.25 2.12 1.28 3.03 5 35 2.07 2.23 1.65 1.97 4.54 1.121.98 0.30 2.54 1.78 3.10 6 42 1.53 1.13 1.87 1.86 3.34 1.40 1.51 0.372.20 1.01 3.17 7 49 1.33 1.09 1.16 1.67 2.23 1.29 1.19 0.12 1.73 0.473.24 8 56 1.56 1.29 1.30 1.28 2.09 1.54 1.38 0.15 1.64 0.41 3.31 9 631.06 0.83 1.39 1.13 2.27 0.97 1.09 0.28 1.46 0.71 4.07 10 70 1.39 1.001.36 1.42 3.51 1.48 1.25 0.22 2.14 1.19 4.14 11 77 1.23 1.15 1.41 1.613.47 1.07 1.26 0.13 2.05 1.26 4.21 12 84 1.29 1.10 1.21 1.23 3.47 1.231.20 0.10 1.98 1.29 4.28 13 91 1.38 0.88 1.10 1.09 3.22 1.38 1.12 0.251.90 1.16 5.05 14 98 1.94 1.01 1.32 1.28 3.76 1.19 1.42 0.47 2.08 1.465.12 15 105 1.54 0.98 1.23 1.37 3.48 1.31 1.25 0.28 2.05 1.24 5.19 16112 1.61 0.94 1.30 1.22 3.98 1.59 1.28 0.34 2.26 1.50 5.26 17 119 1.360.97 1.49 1.48 2.66 1.65 1.27 0.27 1.93 0.64 6.02 18 126 1.40 0.93 0.950.99 3.25 1.16 1.09 0.27 1.80 1.26 6.09 19 133 1.47 1.19 1.33 1.36 3.360.98 1.33 0.14 1.90 1.28 6.16 20 140 1.16 1.25 0.85 3.2* 3.46 1.03 1.090.21 2.25 1.72 6.23 21 147 1.16 1.23 1.26 1.17 5.56 1.53 1.22 0.05 2.752.44 6.30 22 154 1.63 2.02* 1.44 1.41 5.21 1.34 1.54 0.13 2.65 2.21 7.0723 161 1.26 1.04 0.92 1.41 44.82** 1.36 1.07 0.17 1.39 0.04 7.14 24 1681.85 0.9 BLQ 1.5 3.78 1.26 1.38 0.67 2.18 1.39 7.21 25 175 1.69 1 BLQ1.29 3.46 1.3 1.35 0.49 2.02 1.25 7.28 26 182 1.42 1.09* 0.34 1.7 4.481.82 0.88 0.76 2.67 1.57 *re-analysis **re-analysis, abnormal data

FIG. 14 is a graph of the in vivo plasma concentration of risperidone inthe beagle dog study. The lower plot represents the average plasmaconcentration achieved in dogs implanted with one Carbothane® PC-3575Apolyurethane implant (F.M. 620 psi). The upper plot represents theaverage plasma concentration achieved in dogs implanted with twoCarbothane® PC-3575A polyurethane implants (F.M. 620 psi).

EQUIVALENTS

The present disclosure is not to be limited in terms of the particularembodiments described in this application, which are intended asillustrations of various aspects. Many modifications and variations canbe made without departing from the spirit and scope of the disclosure,as will be apparent to those skilled in the art. Functionally equivalentmethods, systems, and apparatus within the scope of the disclosure, inaddition to those enumerated herein, will be apparent to those skilledin the art from the foregoing descriptions. Such modifications andvariations are intended to fall within the scope of the appended claims.The present disclosure is to be limited only by the terms of theappended claims, along with the full scope of equivalents to which suchclaims are entitled. It is to be understood that this disclosure is notlimited to particular methods, reagents, compounds compositions orbiological systems, which can, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting. As will be understood by one skilled in the art, for any andall purposes, such as in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.All references cited herein are incorporated by reference in theirentireties.

1. An implantable drug delivery device, comprising a polyurethane-basedpolymer having polyether-based polyol segments represented by theformula O—(CH₂—CH₂—CH₂—CH₂)_(x)—O— whereby an increase in “x” representsa decrease in Flex Modulus, said polyurethane-based polymer configuredto provide a cylindrically shaped reservoir, wherein the reservoir issealed after being charged with an effective amount of solid formulationcomprising an active agent and one or more pharmaceutically acceptablecarriers, such that the release of the active agent at a substantiallyzero order rate in vitro by diffusion through the polyurethane-basedpolymer generally increases with the selection of the polyurethane-basedpolymers of decreasing Flex Modulus, wherein the active agent isrisperidone, dexamethasone, naltrexone, metolazone, clonidine, orselegiline.
 2. The drug delivery device of claim 1, wherein the activeagent is risperidone.
 3. The drug delivery device of claim 1, whereinthe active agent is dexamethasone.
 4. The drug delivery device of claim1, wherein the active agent is naltrexone.
 5. The drug delivery deviceof claim 1, wherein the active agent is metolazone.
 6. The drug deliverydevice of claim 1, wherein the active agent is clonidine.
 7. The drugdelivery device of claim 1, wherein the active agent is selegiline. 8.The drug delivery device of claim 1, wherein the polyurethane-basedpolymer has a flex modulus of between about 1000 psi and 92,000 psi. 9.The drug delivery device of claim 1, wherein the polyurethane-basedpolymer has a flex modulus of about 1000 psi.
 10. The drug deliverydevice of claim 1, wherein the one or more pharmaceutically acceptablecarriers is selected from the group consisting of croscarmellose,stearic acid, and a combination thereof.
 11. The drug delivery device ofclaim 10, wherein the one or more pharmaceutically acceptable carriersare croscarmellose and stearic acid.
 12. The drug delivery device ofclaim 11, wherein the croscarmellose comprises 10% of the solid drugformulation, and stearic acid comprises 2% of the solid drugformulation.
 13. The drug delivery device of claim 1, wherein thereservoir has a wall thickness of 0.2 mm.
 14. A method of deliveringrisperidone to a subject, comprising implanting an implantable deviceinto the subject, wherein the implantable device comprises apolyurethane-based polymer having polyether-based polyol segmentsrepresented by the formula O—(CH₂—CH₂—CH₂—CH₂)_(x)—O— whereby anincrease in “x” represents a decrease in Flex Modulus, saidpolyurethane-based polymer configured to provide a cylindrically shapedreservoir, wherein the reservoir is sealed after being charged with aneffective amount of solid formulation comprising an active agent and oneor more pharmaceutically acceptable carriers, such that the release ofthe active agent at a substantially zero order rate in vitro bydiffusion through the polyurethane-based polymer generally increaseswith the selection of the polyurethane-based polymers of decreasing FlexFlex Modulus, wherein the active agent is risperidone, dexamethasone,naltrexone, metolazone, clonidine, or selegiline.
 15. The drug deliverydevice of claim 14, wherein the active agent is risperidone.
 16. Thedrug delivery device of claim 14, wherein the active agent isdexamethasone.
 17. The drug delivery device of claim 14, wherein theactive agent is naltrexone.
 18. The drug delivery device of claim 14,wherein the active agent is metolazone.
 19. The drug delivery device ofclaim 14, wherein the active agent is clonidine.
 20. The drug deliverydevice of claim 14, wherein the active agent is selegiline.
 21. Themethod of claim 14, wherein the polyurethane-based polymer has a flexmodulus of between about 1000 psi and 92,000 psi.
 22. The method ofclaim 14, wherein the polyurethane-based polymer has a flex modulus ofabout 1000 psi.
 23. The method of claim 14, wherein the one or morepharmaceutically acceptable carriers is selected from the groupconsisting of croscarmellose, stearic acid, and a combination thereof.24. The method of claim 13, wherein the one or more pharmaceuticallyacceptable carriers are croscarmellose and stearic acid.
 25. The methoddevice of claim 14, wherein the croscarmellose comprises 10% of thesolid drug formulation, and stearic acid comprises 2% of the solid drugformulation.
 26. The method of claim 14, wherein the reservoir has awall thickness of 0.2 mm.